In contrast to physiological programmed cell death, wherein dying cells are rapidly engulfed and digested by phagocytes without inducing inflammation (Nonpatent Document 1), in the excess or non-homeostatic cell death caused by non-infectious stimuli such as irradiation and tissue damage, transient infiltration of neutrophils into tissue is induced (Nonpatent Document 2). The molecular mechanism by which cells recognize this excess or non-homeostatic cell death and respond appropriately has not fully been clarified.
The Toll-like receptor (TLR) family of innate immunity receptors was reported to recognize self-ligands released from dead cells, such as hyaluronan, heat shock proteins (HSPs), uric acid, fibronectin, cardiolipin and nucleosome, as well as DNA/RNA-protein complexes such as small nuclear ribonucleoproteins (snRNPs) (Nonpatent Document 3). Some of these TLR-self-ligand interactions have been shown to be involved in inflammatory diseases.
Although C-type lectins are receptors in a family other than the TLR family, they are capable of mediating the perception of dead cells. These receptors play a distinct role in immunity as pattern-recognizing receptors (PRRs) of pathogen sugar chains. Furthermore, recent evidence has suggested that they may also be capable of recognizing ligands such as proteins, fats, and minerals. In addition to acting as PRRs, some of the C-type lectins expressed in bone marrow cells also function as receptors of dead cells (Nonpatent Document 4). Most of them are receptors of phagocytes that promote the clearance of dead cells.
Of the C-type lectin receptors, Mincle (also known as Clec4e or Clecsf9) is a type-2 transmembrane C-type lectin receptor expressed in macrophages. Previous reports have shown that the transcription of Mincle is elevated with some stimuli and cell stress, and that the expression is regulated by the transcriptional factor NF-IL6 (C/EBPβ) (Patent Document 1, Nonpatent Document 5); however, physiological functions of Mincle and physiological ligands thereof remain unknown.